Triazolopyrimidines and related analogs as HSP90-inhibitors

1. A compound represented by Formula I, or a polymorph, ester, tautomer, enantiomer, diastereomer, pharmaceutically acceptable salt or prodrug thereof,

wherein:

R 1 is halogen, —OR 11 , —SR 11 or lower alkyl;

R 2 is —NHR 8 ;

R 4 is —CHR 12 —, —C(O)—, —C(S)—, —S(O)— or —SO 2 —;

R 5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein:

the aryl group is substituted with 4 to 5 substituents,

the heteroaryl group is substituted with 3 to 5 substituents,

the alicyclic group is substituted with 3 to 5 substituents,

the heterocyclic group is substituted with 3 to 5 substituents, and

the substituents are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR 8 , —OR 8 , —CN, —C(O)OH, —C(O)R 9 , —NO 2 , —NR 8 R 10 , lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl, furanyl, indolyl, and indazolyl, wherein R 8 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;

R 8 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R 9 ;

R 9 is H, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, —NR 10 R 10 , or —OR 11 , wherein R 10 and R 10 taken together optionally form a ring of 3–7 ring atoms and optionally 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;

R 10 is hydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, or lower alkynyl,

R 11 is lower alkyl, lower alkenyl, lower alkynyl, lower heteroaryl or lower aryl; and

R 12 is hydrogen or lower alkyl;

provided that when R 5 is alicyclic, the ring system does not contain any tetra-substituted ring carbons.

2. The compound of claim 1 , or a polymorph, ester, tautomer, enantiomer, diastereomer, pharmaceutically acceptable salt or prodrug thereof, wherein each of said aryl, heteroaryl, alicyclic or heterocyclic group is monocyclic or bicyclic.

3. The compound of claim 1 , or a polymorph, ester, tautomer, enantiomer, diastereomer, pharmaceutically acceptable salt or prodrug thereof wherein:

R 1 is halogen; and

R 2 is —NHR 8 , where R 8 is hydrogen or —C(O)R.

4. The compound of claim 1 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:

R 1 is chioro or bromo,

R 2 is —NHR 8 , where R 8 is hydrogen or —C(O)R 9 ; and

R 4 —CHR 12 —.

5. The compound of claim 1 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:

R 2 is —NHR 8 , where R 8 is hydrogen or —C(O)R 9 ; and

R 4 is —CH 2 —.

6. The compound of claim 1 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:

R 1 is chloro or bromo;

R 2 is —NH 2 ,

R 4 is —CH 2 —; and

R 5 is aryl or heteroaryl, wherein each of the aryl and heteroaryl is monocyclic or bicyclic and the aryl is substituted with 4 or 5 substituents and the heteroaryl is substituted with 3 to 5 substituents.

7. The compound of claim 6 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein R 1 is chloro or bromo, R 2 is —NH 2 , and R 5 is a phenyl having at least four substituents.

8. The compound of claim 6 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein R 1 is chioro or bromo, R 2 is —NH 2 and R 5 is a pyridyl having at least three substituents.

9. The compound of claim 6 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein R 1 is chloro or bromo, R 2 is —NH 2 , and R 5 is 1-oxy-pyridyl (N-oxy-pyridyl) having at least three substituents.

10. The compound of claim 6 , wherein the compound is a member selected from the group below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:

11. The compound of claim 6 , wherein the compound is a member selected from the group below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:

12. The compound of claim 6 , wherein the compound is a member selected from the group below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:

13. The compound of claim 6 , wherein the compound is a member selected from the group below, or a polymorph, tautomer, enantiomers, pharmaceutically acceptable salt or prodrug thereof:

14. The compound of claim 6 , wherein the compound is a member selected from the group below, or a polymorph, tautomer, enantiomers, pharmaceutically acceptable salt or prodrug thereof:

15. The compound of claim 6 , wherein the compound is a member selected from the group below, or a polymorph, tautomer, enantiomers, pharmaceutically acceptable salt or prodrug thereof:

16. The compound of claim 6 , wherein the compound is represented by the formula below, or a polymorph, tautomer, pharmaceutically acceptable salt or prodrug thereof:

17. The compound of claim 6 , wherein the compound is represented by the formula below, or a polymorph, tautomer, pharmaceutically acceptable salt or prodrug thereof:

18. The compound of claim 6 , wherein the compound is represented by the formula below, or a polymorph, tautomer, pharmaceutically acceptable salt or prodrug thereof:

19. The compound of claim 6 , wherein the compound is represented by the formula below, or a polymorph, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:

20. A pharmaceutical composition comprising one or more pharmaceutical acceptable excipient and at least one compound represented by Formula I below, or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof,

wherein:

R 1 is halogen, —OR 11 , —SR 11 or lower alkyl;

R is —NHR 8 ;

R 4 is —CHR 12 —, —C(O)—, —C(S)—, —S(O)— or —SO 2 —;

R 5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein:

the aryl group is substituted with 4 to 5 substituents,

the heteroaryl group is substituted with 3 to 5 substituents,

the alicyclic group is substituted with 3 to 5 substituents,

the heterocyclic group is substituted with 3 to 5 substituents, and

the substituents are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR 8 , —OR 8 , —CN, —C(O)OH, —C(O)R 9 , —NO 2 , —NR 8 R 10 , lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl, furanyl, indolyl, and indazolyl, wherein R 8 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;

R 8 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R 9 ;

R 9 is H, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, —NR 10 R 10 , or —OR 11 , wherein R 10 and R 10 taken together optionally form a ring of 3–7 ring atoms and optionally 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;

R 10 is hydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, or lower alkynyl,

R 11 is lower alkyl, lower alkenyl, lower alkynyl, lower heteroaryl or lower aryl; and

R 12 is hydrogen or lower alkyl;

provided that when R 5 is alicyclic, the ring system does not contain any tetra-substituted ring carbons.

21. The pharmaceutical composition of claim 20 , wherein:

R 1 is halogen;

R 2 is —NH 2 ,

R 4 is —CH 2 —; and

R 5 is aryl or heteroaryl, wherein each of the aryl and heteroaryl is monocyclic or bicyclic and the aryl is substituted with 4 or 5 substituents and the heteroaryl is substituted with 3 to 5 substituents.